The present invention is directed to methods for the preparation of complex chemical libraries to libraries thus prepared and to methods for their employment as pharmaceuticals and pharmaceutical building blocks. Pharmaceutical activity has been shown for libraries prepared in accordance with the present invention. The present compositions are also useful as chemical reagents, having commercial significance, utility and value per se.
From the discovery of penicillin by Fleming in 1940""s there has been a constant search for new antibiotics, which search continues to this day. Although many antibiotics have been discovered, there is an on-going need for the discovery of new antibiotic compounds because of the emergence of drug resistant strains of bacteria. Thus, research on bacterial infection is a perpetual cycle of development of new antibiotics. When penicillin was first discovered, its broad-spectrum antibiotic activity was hailed as the xe2x80x9cmagic bulletxe2x80x9d in fighting many bacterial infections. However, over the years, many strains of bacteria have developed a resistance to penicillin and other currently available antibiotic drugs. No antibiotic drug is effective against all bacterial infections. Many antibiotic drugs available today have narrow-spectrum of activity, that is, they are effective against only few specific types of bacterial infections. Thus, for example, the majority of current antibiotic drugs are ineffective against syphilis and tuberculosis. In addition, some strains of syphilis, tuberculosis and other bacteria have developed resistance to currently available antibiotic drugs, which were effective drugs in the past.
Most bacteria which are resistant to a given drug also exhibit similar resistance to chemically similar drugs. Currently, many antibiotics are based on the xcex2-lactam chemical core structure of penicillin. Although other chemically diverse antibiotics, such as vancomycin, are currently available, it is only a matter of time before the emergence of bacterial strains which will be resistant to all currently available antibiotic drugs. Thus, to prevent a future world-wide epidemic of drug resistant bacterial infections, there is a never ending need for a development of antibiotic drugs with novel chemical structures. This invention addresses this goal among others.
It is, accordingly, an object of this invention to provide novel processes for the preparation of compositions of compounds for use as antibiotics and other pharmaceuticals.
A further object of the invention is to provide products produced by processes herein disclosed for the preparation of pharmaceuticals and other useful chemical species.
Another object of the present invention is to provide complex chemical libraries which are useful, per se as antibiotics, and as other pharmaceutical formulations, as well as research reagents.
A further object of the invention is to provide methods for the creation of complex chemical libraries and for the attainment of increased complexity (albeit complexity following logical, preselected paradigms) in pre-existing chemical libraries.
Yet another object is to provide methods for the identification of useful drugs and reagents.
These and other objects will become apparent to persons of ordinary skill in the art from a review of the present specification and appended claims.
The present invention is directed to methods for preparing chemical libraries and to the useful libraries thus formed. Chemical libraries are known per se for use in the preparation of pharmaceuticals, as research reagents, and as intermediates in the preparation of other useful chemical species. Chemical libraries are commercial products per se and are useful commodities in and of themselves. It has now been found that certain chemical libraries have pharmaceutical use in themselves, exhibiting antibacterial activity and activity in certain other biological assays.
In accordance with the present invention, improved chemical libraries are prepared by reacting a mixture of at least four reactive chemical compounds with a chemical scaffold moiety. This reaction provides a mixture of reaction products. Following such reaction, the scaffold moiety portion of those reaction products is transformed so as to alter either its chemical properties, its electrochemical properties, or both. This transformation of the scaffold moiety portion of the reaction products is accomplished either by the opening of a chemical ring comprising the scaffold, by cyclization of a portion of the scaffold, by appending to the scaffold at least one chemical substituent, or by certain other chemical reactions. Exemplary of such additional reactions is the alteration of the oxidation state of one or more functionalities on the scaffold, alkylation of the scaffold, or acylation of the scaffold. Other chemical, electrochemical, or other reactions which can give rise to alterations in the scaffold can also be used if the scaffold""s chemical or electrochemical properties are changed thereby.
In accordance with certain preferred embodiments, the scaffolds are electrochemically or chemically reduced such as to effect the reduction of a carbonyl moiety, unsaturation or the like. Ring opening reactions are also preferred for use in accordance with the present invention, especially when such rings comprise a macrocycle. It is convenient to employ macrocycles having at least one nitrogen-oxygen bond, since the same are quite labile towards ring opening. Other ring opening reactions may also be used, however.
Other transformations which are within the present invention include nucleophilic substitutions involving the scaffold moieties, especially nucleophilic substitutions involving nitrogen. In accordance with other preferred embodiments, nucleophilic or other substitutions on the scaffold are employed in such a fashion that additional reactive moieties are added thereto. Exemplary additional reactive moieties are amido, imino, and primary and secondary nitrogen functions. It will be appreciated that these functions are capable of further reaction to provide further diversity in chemical libraries in accordance with the present invention.
In accordance with other preferred embodiments of the present invention, the transformed scaffold moiety portions of the mixture of reaction products are reacted with a set of at least four reactive chemical moieties to form a further library of chemical compounds.
It is convenient to perform the methods of the present invention in an iterative fashion whereby an original scaffold moiety is sequentially and repeatedly altered or transformed and then reacted with sets of chemical reactant species to form very complex chemical libraries. The present invention is also directed to chemical libraries prepared in accordance with the methods of the present invention. The libraries have been found to have antibacterial and activity such that antibacterial compositions comprising chemical libraries prepared in accordance with the present invention are provided. Other pharmaceutical utility exists for the compositions of the invention including antifungal, biological inhibitory and other properties.